Published online before print January 26, 2004, doi: 10.1161/01.HYP.0000116303.71408.c2
(Hypertension. 2004;43:661.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
PPAR
Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice
From the Departments of Internal Medicine (M.J.R., S.P.D., S.M., F.M.F, C.D.S.), Pharmacology (F.M.F.), and Physiology and Biophysics (C.D.S.), Cardiovascular Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
Correspondence to Curt D. Sigmund, Ph.D. Professor, Department of Internal Medicine, 3181 MERF, University of Iowa, Department of Internal Medicine Iowa City, IA 52242 E-mail Curt-Sigmund{at}uiowa.edu
The peroxisome proliferator activated receptor (PPAR
) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R+A+). Rosiglitazone decreased systolic (138±5 versus 128±5 mm Hg) and mean blood pressure (145±5 versus 126±7 mm Hg) of R+A+ mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R+A+ mice when compared with littermate controls (RA-). There were no effects of rosiglitazone on RA- mice; however, relaxation to acetylcholine (49±10 versus 82±9% at 100 µmol/L) and nitric oxide (51±11 versus 72±6% at 10 µmol/L) was significantly improved in treated R+A+ mice. Rosiglitazone treatment of R+A+ mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R+A+ and RA- mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPAR-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitor N
-nitro-L-arginine methyl ester (200 µmol/L) or the PPAR antagonist bisphenol A diglycidyl ether; 4,4'-isopropylidenediphenol diglycidyl ether (100 µmol/L). These data suggest that in addition to potential genomic regulation caused by PPAR activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.
Key Words: nitric oxide • angiotensin • endothelin • carotid
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